The innate tissue-protective response is characterized by distinct stages in which pro- and antiinflammatory cytokines and their receptors are temporally and spatially distinct. Stage 1: Pathogen-associated molecular patterns, hypoxia and molecular injury signals trigger the innate immune response driven by proinflammatory cytokines. Stage 2: Proinflammatory cytokines are produced within the injury region and diffuse into the surrounding normal tissue, priming it for self-destruction (the penumbra). Stage 3: Simultaneously, upregulation of the TPR by proinflammatory cytokines occurs within the penumbra. Macrophages recruited into the damaged area amplify injury, and the lesion progressively enlarges as the inflammatory components self-amplify and diffuse outward, causing additional damage. The high levels of proinflammatory cytokines suppress production of EPO, the ligand of the TPR. Stage 4: EPO is produced at the lesion periphery, where proin-flammatory cytokine concentrations are lower, and diffuses inward, engaging the TPR, which in turn inhibits proinflammatory cytokine production and rescues cells within the penumbra from apoptosis. Stage 5: The lesion size is contained at the boundary defined by the effective inhibition of apoptosis and unrescuable cellular destruction. Stage 6: In the subacute phase, tissue receptor activation also mobilizes tissue-specific and endothe-lial stem cells that participate in angiogenesis and other aspects of repair. Stages 1–3 occur rapidly (minutes to hours), while stages 4–6 occur with a substantial time delay (hours to days).